Modern postoperative pain control focuses on early mobilization and rapid discharge of patients following surgery. Although minimally invasive of nature, arthroscopic procedures do produce pain and inflammation. As a result patients may be prevented from returning to work for weeks after surgery.
Findings have shown that aggressive pain management, including local intra-articular drug therapy, in the early postoperative period can improve convalescence after surgery significantly.
Over the years the efficacy of a significant number of drugs and drug combinations to provide pain relief after intra-articular injection has been investigated. Efficacious intra-articular monotherapeutic approaches include (i) NSAIDs, (ii) local anaesthetics, and (iii) opiates (e.g. morphine). Following arthroscopic procedures promising pain alleviating effects of different intra-articular multimodal analgesic regimens have been reported. Most combinations used consisted of 2-3 drugs selected from opiates, local anaesthetics and anti-inflammatory agents (NSAIDs or corticosteroids) (ref. 1, 2).
Looking to future intra-articular multimodal therapies, particular attention needs to be paid to tailor the duration of action of the individual therapeutic agents whilst keeping the dose of administered compounds to a minimum.
Treatment of e.g. inflammation with NSAIDs is difficult to attain in a site-specific manner. Consequently, a systemic approach is usually employed, where an oral dose is spread through-out the body, thereby limiting the effective dose at the injured or inflamed site, and increasing the emergence of side effects due to high concentrations of NSAIDs in other areas of the body. Attempts to inject the NSAID locally at the site of treatment will only be effective for a few hours, by which time the water-soluble injected drug will, for practical purposes, have diffused out of the joint space, and into the general circulation. This short half-life of intra-articular disappearance of NSAIDs and other small-molecule drugs, which have relatively high water solubility at and around physiological pH, is inhibitive for a continuous release/depot effect.
Simple depot suspensions may be thought to be a preferred way to deliver an immobilised drug since a high drug load can be achieved and minimal pharmaceutical excipients are needed. However, in spite of the relative simplicity of this formulation type compared to more advanced and complex controlled release drug delivery systems, the formulation of (physically) stable injectable suspensions with good shelf-life poses considerable manufacturing challenges.
The problem of administering depot formulations to joints has previously been attempted to be solved by injecting for example suspensions made from steroid esters. Various long-acting steroid ester formulations (aqueous microcrystalline suspensions) are marketed for intra-articular injection. The duration of action of such injectables are 2-6 weeks and thus not indicated for postoperative pain control following minor arthroscopic surgery, which is typically 1-7 days. The drawbacks of using a microcrystalline suspension include that suspensions are difficult to sterilize (e.g. sterilization by filtration is excluded) and that the particle size distribution of the suspended particles may change over time, thereby also changing the in vivo drug release profile. Thus, the formulation of (physically) stable injectable suspensions with good shelf-life poses considerable manufacturing challenges.
Alternatives to microcrystalline depot formulations as described above are injecting a poorly water-soluble salt of the drug solubilised in a co-solvent, which is then precipitated in situ at the injected site (upon contact with water/the biologic fluid, in which the salt is poorly soluble). The drawbacks of this approach is that the release profile is difficult to control—either the release is too fast (1-2 hours) or too slow.
Hydrogels have also been employed, as a possible depot formulation principle. One of the drawbacks of hydrogels is that some do leave behind insoluble residual material in the joint, which is undesirable. Further, a hydrogel does not enable simultaneous release of analgesics (local anaesthetics or opiates over a 24 h period) and anti-inflammatory agents (NSAIDs or corticosteroids over about 7 days), which has been found to improve convalescence after surgery significantly.
There is thus a need in the art for intra-articular depot formulations that may be tailored to have a release profile over 1-10 days.
Further, there is a need for a formulation that does not leave behind insoluble residual material in the joint.
Further, there is a need for a formulation that allows the tailoring of different release profiles in a multimodal regimen.